ClinVar Miner

Submissions for variant NM_000360.4(TH):c.1282C>T (p.Gln428Ter)

dbSNP: rs786204540
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169247 SCV000220529 likely pathogenic Autosomal recessive DOPA responsive dystonia 2014-07-18 criteria provided, single submitter literature only
Invitae RCV000169247 SCV001584620 pathogenic Autosomal recessive DOPA responsive dystonia 2023-11-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln459*) in the TH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TH are known to be pathogenic (PMID: 22264700, 24753243). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with encephalopathy (PMID: 20430833). ClinVar contains an entry for this variant (Variation ID: 188890). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169247 SCV002556256 pathogenic Autosomal recessive DOPA responsive dystonia 2022-06-29 criteria provided, single submitter clinical testing Variant summary: TH c.1375C>T (p.Gln459X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250386 control chromosomes. c.1375C>T has been reported in the literature in at least one individual affected with tyrosine hydroxylase deficiency in the compound heterozygous state (Willemsen_2010). The variant was studied in vitro and was shown to have no measurable enzyme activity (Fossbakk_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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